Clinical and molecular dissection of CAR T cell resistance in pancreatic cancer.

ABSTRACT: Patients with advanced pancreatic ductal adenocarcinoma (PDAC) have a median survival of less than a year, highlighting the urgent need for treatment advancements. We report on a phase 1 clinical trial assessing the safety and feasibility of intravenous and local administration of anti-mesothelin CAR T cells in patients with advanced PDAC. While therapy is well tolerated, it demonstrates limited clinical efficacy. Analyses of patient samples provide insights into mechanisms of treatment resistance. Single-cell genomic approaches reveal that post-infusion CAR T cells express exhaustion signatures, including previously identified transcription factors ID3 and SOX4, and display enrichment for a GZMK⁺ phenotype. Single knockout of ID3 or SOX4 enhances efficacy in xenograft models, t

SUBMITTER: Aznar MA 

PROVIDER: S-EPMC12490220 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature